Functional Significance of Antibody Isotype in Protection Against HIV

The constant heavy chain-domain affects antibody affinity and fine specificity, challenging the paradigm that the only variable regions contribute to antigen binding. Hence, the broadly-neutralizing anti-HIV-1 2F5-IgG1 transformed into IgA2 had higher antigen-affinity, different antiviral activities, although both isotypes acted synergistically to neutralizing HIV-1 transfer from Langerhans to CD4+T-cells, one initial step in mucosal HIV-1 entry. Isotype differences correlate with unique epitope specificity (Tudor, PNAS, 2013). Here, we investigate the exclusive role of CH1-domain in antibody specificity/functions. We constructed IgG1-Fabs from two IgA1-Fabs specific for gp41 we previously constructed from vaginal B cells from highly HIV-exposed individuals that remains seronegative (ESN) despite unprotected intercourse with HIV-positive partners (Tudor, Mucosal Immunol, 2009). Fab-IgA2 and IgG1 differ only by their CH1. The two IgA1-Fabs had higher affinity for gp41 clade-B but also clade-A, and C cross-clade, compared to corresponding IgG1-Fabs. Functionally, IgA1-Fabs neutralized more robustly CD4+T-cell clade-B-HIV-1 infection and transfer from Langerhans to CD4+T-cells. Fabs also strongly neutralized clade-A and C-HIV-1 infection, demonstrating cross-clade antiviral activities. Epitope mapping performed by random peptide library screening and in-silico docking on gp41-envelope indicate that IgAs and corresponding IgGs recognize distinct 3-Dimensional-epitopes. Altogether, these studies clearly demonstrate that the exclusive CH1-region contributes to shape antibody epitope specificity, affinity and functional activities. More, IgA and IgG can have different but complementary anti-viral activities. We now design a vaccine based on protective (ESN) IgG/A-epitopes for raising a mucosal IgA/IgG-mixed response with complementary activities efficient in blocking sexual HIV-1-transmission. Such strategy should apply to other sexually-transmitted infections.